Sexual transmission is the primary route by which human immunodeficiency virus (HIV) is acquired. In the prevailing hypothesis about the initial events of infection, dendritic cells (DC) serve as a major vehicle for trafficking HIV across the mucosa and to secondary lymphoid organs, such as lymph nodes (LN), where robust viral replication can be initiated in T-cells. A DC-specific molecule, DC-SIGN, appears to be involved in binding and transfer of infectious HIV to CD4+ T-cells, although it does not function as an entry receptor. The SIV macaque model represents the best experimental system for examining the significance of DC-SIGN in transmission. However, lack of suitable reagents for studying DC-SIGN's role in vivo has hampered efforts in this area. In this application, we propose to develop reagents for the SIV macaque model that will allow us to test the hypothesis that virus attachment to DC mediated by DC-SIGN plays a significant role in transmission and dissemination of SIV. The following aims have been proposed for this study: Aim 1: To develop monoclonal antibodies against macaque DC-SIGN. To develop monoclonal antibodies against native SIV Env. Aim 2: To determine whether macaque DC-SIGN mediates transmission of SIV or SHIV to T-cells in vitro, and to determine if anti-DC-SIGN monoclonal antibodies or anti-Env antibodies will neutralize binding of virus to DC-SIGN and subsequent transmission of T-cells. The development of monoclonal antibodies to DC-SIGN will provide critical reagents for examining the localization of DC-SIGN+, DC populations in tissues. Furthermore, identifying monoclonal antibodies to DC-SIGN as well as the SIV envelope that neutralize virus attachment to DC-SIGN and subsequent transfer to CD4+ T-cells will serve as a basis for vaccine and passive immunotherapy strategies aimed at preventing infection.